Radiation-induced exosomes promote oral squamous cell carcinoma progression via enhancing SLC1A5-glutamine metabolism.

BACKGROUND: Radiotherapy (RT) can drive cancer cells to enter a state of cellular senescence in which cells can secrete senescence-associated secretory phenotype (SASP) and produce small extracellular vesicles (sEVs) to interact with cells in the tumor microenvironment (TME). Tumor-derived sEVs that are taken up by recipient cells contribute to cancer cell metabolic plasticity, resistance to anticancer therapy, and adaptation to the TME. However, how radiation-induced sEVs support oral squamous cell carcinoma (OSCC) progression remains unclear. METHODS: Beta-galactosidase staining and SASP mRNA expression analysis were used to evaluate the senescence-associated activity of OSCC cells after irradiation. Nanoparticle tracking analysis was performed to identify radiation-induced sEVs. Liquid chromatography-tandem mass spectrometry (LC-MS) was used to explore changes in the levels of proteins in radiation-induced sEVs. Cell Counting Kit-8 and colony formation assays were performed to investigate the function of radiation-induced SASP and sEVs in vitro. A xenograft tumor model was established to investigate the functions of radiation-induced sEVs and V-9302 in vivo as well as the underlying mechanisms. Bioinformatics analysis was performed to determine the relationship between glutamine metabolism and OSCC recurrence. RESULTS: We determined that the radiation-induced SASP triggered OSCC cell proliferation. Additionally, radiation-induced sEVs exacerbated OSCC cell malignancy. LC-MS/MS and bioinformatics analyses revealed that SLC1A5, which is a cellular receptor that participates in glutamine uptake, was significantly enriched in radiation-induced sEVs. In vitro and in vivo, inhibiting SLC1A5 could block the oncogenic effects of radiation-induced sEVs in OSCC. CONCLUSION: Radiation-induced sEVs might promote the proliferation of unirradiated cancer cells by enhancing glutamine metabolism; this might be a novel molecular mechanism underlying radiation resistance in OSCC patients.

The abnormalities of lipid metabolism in children and adolescents with major depressive disorder and relationship with suicidal ideation and attempted suicide.

Background: Major depressive disorder (MDD) is a widespread health issue in many countries, which has an extremely negative impact on the health of children and adolescents in particular. In the context of depression and metabolic disorders, dyslipidemia and metabolism-related problems become more prominent comorbidities. However, they continue to be the main barrier to the successful recovery of the clinical progress. In this study we investigated the rate of dyslipidemia, additional risk factors among Chinese children and adolescents with MDD, and association of the suicidal behavior with lipid levels. Methods: The study took 756 people from the Third People's Hospital of Fuyang between January 2020 and December 2021, aged between 8 and 18, with major depressive disorders diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). We determined the FBG (fasting blood glucose) and lipid parameters in all subjects and also investigated the history of suicidal ideation, the cases of attempted suicide, and the scores of depressive symptoms. Sociodemographic and clinical data were gathered and analyzed using the SPSS-23.0 version. Results: The prevalence of hypercholesterolemia, hypertriglyceridemia, high LDL-C, and low HDL-C were 5.42 % (41/756), 10.58 % (80/756), 3.84 % (29/756) and 5.42 % (41/756) respectively. For hypercholesterolemia and hypertriglyceridemia, they were positive associated with suicidal ideation and suicide attempts, and the positive correlation is shown between low HDL-C levels and suicide attempts. Nevertheless, non-ideation and inversely suicidal attempts were not discovered among high-LDL-C subjects. Logistic analysis showed that high levels of FBG (OR = 2.86, 95 % CI: 1.31-6.25, P = 0.008) and worse LDL-C (OR = 357.82, 95 % CI: 66.16-1935.10, P < 0.001) are the independent associated factors for hypercholesterolemia. More hospitalizations (OR = 1.89, 95 % CI: 1.07-3.35, P = 0.028), obesity (OR = 2.55, 95 % CI: 1.25-5.18, P = 0.010), high levels of TC (OR = 2.15, 95 % CI: 1.03-4.48, P = 0.042), and higher doses of antidepressants (OR = 1.02, 95 % CI: 1.00-1.04, P = 0.029) were independently associated factors for hypertriglyceridemia, while high levels of HDL-C (OR = 0.11, 95 % CI: 0.04-0.31, P < 0.001) were protective factors. In addition, high levels of TC (OR = 113.94, 95 % CI: 20.01-648.85) were statistically different (P < 0.001) and suggested that the factor was significantly related to high LDL-C. Meanwhile, older age (OR = 1.25, 95 % CI: 1.02-1.52, P = 0.030) and high levels of TG (OR = 3.00, 95 % CI: 1.98-4.55, P < 0.001) were independent factors contributing to low HDL-C. Conclusion: The high prevalence of dyslipidemia in childhood and adolescence among children and adolescents with depressive disorder has become a public health issue. Hypercholesterolemia and hypertriglyceridemia showed a positive correlation with suicidal thoughts and suicidal attempts. Monitoring the incidence of suicidal thoughts and attempts among them would carry some predictor meaning in therapy and for jumping back to health.

The prevalence of underweight and obesity in Chinese children and adolescents with major depressive disorder and relationship with suicidal ideation and attempted suicide.

Background: The high rates of obesity and suicide have become serious public health problems worldwide, especially in children and adolescents with major depressive disorder (MDD). This research aimed to explore the rates of underweight, overweight or obesity, suicidal ideation and attempted suicide in hospitalized children and adolescents with MDD. Then, we analyzed the correlation between underweight or obesity and suicidal ideation and attempted suicide, and finally obtained the independent influencing factors of underweight or obesity. Methods: A total of 757 subjects in the Third People's Hospital of Fuyang from January 2020 to December 2021 were enrolled in this study. According to the underweight, overweight and obesity screening table for school-age children and adolescents published and implemented by the health industry standard of China, all subjects were divided into different body mass index (BMI) categories. We measured fasting blood glucose (FBG) and lipid levels in all subjects and assessed suicidal ideation, attempted suicide, and the severity of depressive symptoms. The socio-demographic and clinical data were collected and analyzed by SPSS 22.0. Results: The rates of underweight, overweight, obesity, suicidal ideation and attempted suicide were 8.2% (62/757), 15.5% (117/757), 10.4% (79/757), 17.2% (130/757), and 9.9% (75/757), respectively. Correlation analysis indicated that BMIs level was positively correlated with age, age of first hospitalization, total duration of disease, number of hospitalizations, FBG, TG (triglyceride), TC (total cholesterol), LDL (low density lipoprotein), and negatively correlated with HDL (high density lipoprotein). Binary logistic regression analysis showed that male and high level of HDL were risk factors for MDD inpatients with underweight, while high level of TG was a protective factor. Meanwhile, higher levels of FBG, TG and CGI-S were risk factors and suicidal ideation and high dose of antidepressant drugs were protective factors for obesity in children and adolescents with MDD. Conclusion: The prevalence of underweight, obesity, suicidal ideation and attempted suicide were high in children and adolescents with MDD, and severe depressive symptoms are independent risk factors for obesity, while suicidal ideation and high dose of antidepressants may be protective factors for obesity.

TIPE3 represses head and neck squamous cell carcinoma progression via triggering PGAM5 mediated mitochondria dysfunction.

Mitochondria are essential organelles in balancing oxidative stress and cell death during cancer cell proliferation. Rapid tumor growth induces tremendous stress on mitochondria. The mammalian tumor necrosis factor-α-induced protein 8-likes (TIPEs) family plays critical roles in balancing cancer cell death and survival. Yet, the roles of TIPEs in HNSCC tumorigenesis and mitochondria stress maintenance is unclear. Based on an integrative analysis of public HNSCC datasets, we identified that the downregulation of TIPE3 via its promoter hypermethylation modification is the major event of TIPEs alterations during HNSCC tumorigenesis. Low expression levels of TIPE3 were correlated with high malignancy and poor clinical outcomes of HNSCC patients. Restoring TIPE3 represses HNSCC proliferation, migration, and invasion in vitro and in vivo, while silencing TIPE3 acted on an opposite way. Mechanistically, TIPE3 band to the PGAM5 and electron transport chain (ETC) complex. Restoring TIPE3 promoted PGAM5 recruiting BAX and dephosphorylating p-DRP1(Ser637), which triggered mitochondrial outer membrane permeabilization and fragmentation. Ultimately, TIPE3 induced ETC damage and oxygen consumption rate decrease, ROS accumulation, mitochondrial membrane potential depolarization, and cell apoptosis. Collectively, our work reveals that TIPE3 plays critical role in maintaining mitochondrial stress and cancer cell progression in HNSCC, which might be a potential therapeutic target for HNSCC patients.

BASP1 is a prognostic biomarker associated with immunotherapeutic response in head and neck squamous cell carcinoma.

Backgrounds: Immunotherapy is effective in a subset of head and neck squamous cell carcinoma (HNSCC). However, the unfavorable response rate and inadequate biomarkers for stratifying patients have primarily limited its clinical application. Considering transcriptional factors (TFs) play essential roles in regulating immune activity during HNSCC progression, we comprehensively analyzed the expression alterations of TFs and their prognostic values. Methods: Gene expression datasets and clinical information of HNSCC were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) repository. Then, Brain abundant membrane attached signal protein 1 (BASP1) was screened out of differentially expressed TFs by univariate and multivariate survival analysis. Tumor immune dysfunction and exclusion (TIDE) was applied to analyze the response to immunotherapy of BASP1high/low patients. Meanwhile, GO, KEGG and GSEA analyses were used to enrich the pathways between the BASP1high and BASP1low groups. Single-sample gene set enrichment analysis (ssGSEA), CIBERSORT, EPIC and quanTiseq algorithms were applied to explore immune infiltrations. Also, immune cycle analysis was conducted by ssGSEA. Additionally, lipid peroxidation, glutathione and reactive oxygen species were performed to detect the ferroptosis alternations. Results: BASP1 was upregulated and associated with poor survival in HNSCC patients. BASP1high patients exhibited better response rates to anti-PD-1 immunotherapy and higher expressions of immune checkpoint inhibitors. GO, KEGG and GSEA analyses indicated that the expression of BASP1 was related to several immune-related pathways and immunogenic ferroptosis signature. The infiltration of activated CD8+ T cells was authenticated to be decreased in BASP1high patients. Furthermore, BASP1 was identified to be positively correlated with T cell dysfunction and immune escape. Moreover, silencing BASP1 triggered ferroptosis in HNSCC cells, representing as increased LDH, lipid peroxidation and ROS levels, and reduced glutathione synthesis. Conclusions: We demonstrated that BASP1 suppressed immunogenic ferroptosis to induce immunosuppressive tumor microenvironment. BASP1 plays a critical role in immune response, and might be a promising classifier for selecting HNSCC patients who benefit from current immunotherapy.

Carboxylesterase 2 induces mitochondrial dysfunction via disrupting lipid homeostasis in oral squamous cell carcinoma.

OBJECTIVE: Oral squamous cell carcinoma (OSCC) is characterized by high recurrence and metastasis and places a heavy burden on societies worldwide. Cancer cells thrive in a changing microenvironment by reprogramming lipidomic metabolic processes to provide nutrients and energy, activate oncogenic signaling pathways, and manage redox homeostasis to avoid lipotoxicity. The mechanism by which OSCC cells maintain lipid homeostasis during malignant progression is unclear. METHODS: The altered expression of fatty acid (FA) metabolism genes in OSCC, compared with that in normal tissues, and in OSCC patients with or without recurrence or metastasis were determined using public data from the TCGA and GEO databases. Immunohistochemistry was performed to examine the carboxylesterase 2 (CES2) protein level in our own cohort. CCK-8 and Transwell assays and an in vivo xenograft model were used to evaluate the biological functions of CES2. Mass spectrometry and RNA sequencing were performed to determine the lipidome and transcriptome alterations induced by CES2. Mitochondrial mass, mtDNA content, mitochondrial membrane potential, ROS levels, and oxygen consumption and apoptosis rates were evaluated to determine the effects of CES2 on mitochondrial function in OSCC. RESULTS: CES2 was downregulated in OSCC patients, especially those with recurrence or metastasis. CES2high OSCC patients showed better overall survival than CES2low OSCC patients. Restoring CES2 expression reduced OSCC cell viability and suppressed their migration and invasion in vitro, and it inhibited OSCC tumor growth in vivo. CES2 reprogrammed lipid metabolism in OSCC cells by hydrolyzing neutral lipid diacylglycerols (DGs) to release free fatty acids and reduce the membrane structure lipid phospholipids (PLs) synthesis. Free FAs were converted to acyl-carnitines (CARs) and transferred to mitochondria for oxidation, which induced reactive oxygen species (ROS) accumulation, mitochondrial damage, and apoptosis activation. Furthermore, the reduction in signaling lipids, e.g., DGs, PLs and substrates, suppressed PI3K/AKT/MYC signaling pathways. Restoring MYC rescued the diminished cell viability, suppressed migratory and invasive abilities, damaged mitochondria and reduced apoptosis rate induced by CES2. CONCLUSIONS: We demonstrated that CES2 downregulation plays an important role in OSCC by maintaining lipid homeostasis and reducing lipotoxicity during tumor progression and may provide a potential therapeutic target for OSCC.

Association of higher plasma leptin levels with HOMA-IR index, high sensitivity C-reactive protein and glycolipid metabolism in patients with chronic schizophrenia: A multi-center cross-sectional study.

Background: Previous research has revealed that plasma leptin levels were closely related to glycolipid metabolism in schizophrenic patients. Insulin resistance (IR) and high sensitivity C-reactive protein (hs-CRP) were involved in glucolipid metabolism disorders. This study explored the correlation between plasma higher leptin levels, homeostasis model assessment of insulin resistance (HOMA-IR) index, hs-CRP and glycolipid metabolism in patients with chronic schizophrenia (CS). Methods: 322 subjects were enrolled, and the psychopathological symptoms of each patient were assessed by a 30-item Positive and Negative Syndrome Scale (PANSS-30). Patients' plasma leptin levels were measured by enzyme-linked immunosorbent assay (ELISA). Fasting blood glucose (FBG) levels were determined by oxidase method. Insulin levels were tested by electrochemiluminescence, and hs-CRP levels were tested by immunoturbidimetry. IBM SPSS 22.0 was used for data analysis. Results: Compared to the lower leptin group, patients in the higher leptin group had significantly higher body mass index (BMI), total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL-C), insulin, HOMA-IR and hs-CRP levels; and lower negative factor scores, cognitive factor scores, and PANSS total scores (P < 0.05). Plasma leptin levels in CS patients were positively correlated with BMI, TC, TG, LDL-C, insulin, HOMA-IR and hs-CRP levels, and were negatively correlated with gender (male = 1, Female = 2), positive factor scores, negative factor scores, cognitive factor scores and PANSS total scores. Multiple linear regression analysis revealed that gender, BMI, positive factor scores, PANSS total scores, FBG, LDL-C, insulin, HOMA-IR and hs-CRP levels were independent influencing factors of leptin levels in CS patients (P < 0.05). Conclusion: Gender, BMI, positive factor scores, PANSS total scores, FBG, LDL-C, insulin, HOMA-IR and hs-CRP levels were independent influencing factors of plasma leptin levels in CS patients. Plasma leptin, HOMA-IR and hs-CRP levels should be measured regularly in CS patients to prevent or treat the disorders of glucose and lipid metabolism comorbidity with schizophrenia patients in clinical diagnosis and treatment.

Physical activity levels associated with insomnia and depressive symptoms in middle-aged and elderly patients with chronic schizophrenia.

Background: Previous evidence suggested that physical activity had beneficial effects on psychopathological symptoms, insomnia, or depressive symptoms in people with schizophrenia. This study investigated the association between physical activity levels and insomnia and depressive symptoms in middle-aged and elderly hospitalized patients with chronic schizophrenia (CS). Methods: 179 participants were enrolled. We used the 30-item Positive and Negative Syndrome Scale (PANSS-30) to assess the psychopathological symptoms. We used the Insomnia Severity Index scale (ISI) and 17-item Hamilton Depression Scale (HAMD-17) to evaluate insomnia and depressive symptoms. Daily physical activity time less than 30 min, within 30-60 min, and more than 60 min were defined as physical inactivity, moderate physical activity, and vigorous physical activity, respectively. The Chi-square test, analysis of variance (ANOVA), and Mann-Whitney U-test were applied for categorical, continuous, and non-normal distribution variables, respectively. The Pearson or Spearman's correlation analyses were utilized to examine the association between physical activity levels, ISI total scores, HAMD total scores, and socio-demographic and clinical variables. Finally, socio-demographic variables with a P-value < 0.05 in the comparison between insomnia/depressive group and non-insomnia/depressive group were considered for inclusion in binary logistic regression analysis to determine the relationship between physical activity levels and insomnia or depressive symptoms. Results: The ISI total scores (r = -0.247, P = 0.001) and HAMD total scores (r = -0.312, P < 0.001) were negatively correlated with physical activity levels. Logistic regression analysis revealed that older age, higher depressive factor scores, and lower physical activity level were influential factors of insomnia symptoms in CS patients (P < 0.05). In addition, vigorous physical activity (compared with physical inactivity) and higher negative and depressive factor scores were independently associated with depressive symptoms in CS patients (P < 0.05). Conclusion: Physical activity levels were influential factors in comorbid insomnia and depressive symptoms in CS patients. Given the benefits of physical activity, it should be strengthened as a routine adjunct to clinical treatment or psychiatric care so as to improve the physical and mental health of patients with psychiatric symptoms.